Abstract This proposal represents a continuation of a body of work that our laboratory has undertaken to examine the cognitive consequences of alcohol abuse in veterans. Alcohol misuse is a costly and functionally devastating problem that is pervasive among America's veterans, with nearly two and a half times the lifetime prevalence of alcohol-related disorders of nonveterans. Our laboratory has pioneered the use of the eyeblink classical, or Pavlovian, conditioning paradigm as a behavioral biomarker for neuropathological changes in the brain of male and female alcoholics. Our work from the prior funding period examined the acquisition of classically conditioned eyeblink responses to study the consequences of heavy drinking in abstinent chronic alcoholic individuals. This paradigm, based on Pavlovian conditioning as an index of a fundamental unit of learning, has well documented neural correlates in animal models, and has proven itself to be very sensitive to even subtle alterations in human neuropsychological disorders. Our data demonstrate that abstinent alcoholics are differentially impaired in the acquisition of these classically conditioned eyeblink responses. Now, using advanced high resolution imaging and analysis techniques, we have begun to identify alcohol-related degeneration of white matter microstructure using diffusion tensor imaging and have found associations between white matter integrity and performance on eyeblink classical conditioning. Preliminary data also reveal bilateral cortical thickness reductions in alcoholics compared to control participants in brain regions that are known to support eyeblink conditioning. The present study proposes to confirm and extend these preliminary observations in a comprehensive study examining the impact of heavy alcohol use on brain structure (using DTI maps of tissue microstructure and cortical thickness and regional brain volumes to characterize gray matter deterioration), and the associated impact of this deterioration on cognition using performance on eyeblink classical conditioning as a sensitive behavioral biomarker. Elevated cerebrovascular risk is a common comorbid condition of heavy alcohol use that impacts many of the same brain regions and cognitive functions that are impacted by abuse. It is likely that comorbid CVD risk contributes significantly to the degenerative neural environment and associated cognitive decline observed in alcoholics. Thus we will include a control group of normal drinkers with a matched distribution of CVD risk to the heavy alcohol drinkers to evaluate the independent and synergistic effects of CVD risk and alcohol. The successful completion of the aims proposed will add to our knowledge of the neuropsychology of alcoholism by clarifying the relative roles of the cerebellum, medial temporal lobe, frontal cortex and underlying white matter as they relate to the acquisition of new learning within the context of an extremely well understood learning task. We feel the hypothesized changes in brain structure and associated impairments in new learning underlie some of the intractable behavioral problems that characterize alcoholism. PUBLIC HEALTH RELEVANCE: Relevance to VA Patient Care Mission Alcohol abuse is a costly and functionally devastating problem that is pervasive among America's veterans. Prevalence rates of alcohol-related disorders among veterans are nearly two and a half times the lifetime prevalence of alcohol-related disorders of nonveterans. Because of the direct impact alcohol may have on cognitive function and treatment, there is a fundamental need for a more complete understanding of the cognitive sequelae of alcohol use and misuse in both male and female veterans. Using classical conditioning methods, our data demonstrate that abstinent alcoholics are differentially impaired in the acquisition of these classically conditioned eyeblink responses and suggest that the pattern of deficits observed may underlie some of the intractable behavioral problems that characterize alcoholism.